The function of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and the expression of brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of post-traumatic stress disorder (PTSD). This study aims to explore the role of the HCN1 channel, BDNF, and mTOR in the actions of PTSD and to examine whether synaptic transmission or plasticity is involved in the regulation of this disease. In the present study, rats were exposed to the single prolonged stress and electric foot shock (SPS&S) procedure, which can induce PTSD-like behaviors in rats. ZD7288 was administered by intracerebroventricular (i.c.v.) injection to one experimental group to inhibit the function of the HCN1 ion channel while 8-Br-cAMP was administered to another group to activate the function of the HCN1 ion channel. A series of behavioral tests and biochemical assessments of certain proteins (HCN1, BDNF, and pmTOR) and synaptic ultrastructure in the prefrontal cortex (PFC) and hippocampus (Hip) were then conducted. The SPS&S procedure induced apparent PTSD-like symptoms in rats. The administration of ZD7288 reduced the immobility time and escape latency time in the forced swim test (FST) and water maze test (WMT) with a decreased level of HCN1, upregulated BDNF-mTOR signaling pathways in the PFC and Hip, and synaptic ultrastructure changes in the PFC. In contrast, the administration of 8-Br-cAMP, which led to a higher level of HCN1 in PFC and Hip, resulted in a decreased number of entries to the open arms without significant change in total arm entries in the elevated plus maze test (EPMT) as well as a shorter center square distance and total distance in the open field test (OFT). Extended escape latency time was also observed in the WMT although there was no alteration of BDNF-mTOR signaling pathways and synaptic ultrastructure in the PFC and Hip. Overall, the inhibition of HCN1, which can alleviate PTSD-like behavior of rats by relieving depression and improving learning ability, may be related to the upregulated BDNF-mTOR signaling pathways and synaptic transmission.

超极化激活的环核苷酸门控通道1（HCN1）的功能和脑源性神经营养因子（BDNF）的表达可能参与了创伤后应激障碍（PTSD）的发病机制。本研究旨在探讨 HCN1 通道、BDNF 和 mTOR 在 PTSD 作用中的作用，并检查突触传递或可塑性是否参与了该疾病的调节。在本研究中，大鼠暴露于单一的长时间压力和足部电击 (SPS&S) 程序，可诱导大鼠出现 PTSD 样行为。ZD7288通过脑室内（icv）注射给予一个实验组以抑制HCN1离子通道的功能，而将8-Br-cAMP给予另一组以激活HCN1离子通道的功能。然后对前额叶皮层 (PFC) 和海马 (Hip) 中的某些蛋白质（HCN1、BDNF 和 pmTOR）和突触超微结构进行了一系列行为测试和生化评估。SPS&S 程序在大鼠中引起明显的 PTSD 样症状。ZD7288 的给药减少了强迫游泳试验 (FST) 和水迷宫试验 (WMT) 中的不动时间和逃逸潜伏期，HCN1 水平降低，PFC 和髋关节中的 BDNF-mTOR 信号通路上调，突触超微结构变化在 PFC 中。相比之下，给予 8-Br-cAMP 会导致 PFC 和髋关节中 HCN1 水平升高，导致进入张开臂的次数减少，但在高架十字迷宫测试 (EPMT) 中进入的总臂数没有显着变化，并且在旷场测试 (OFT) 中的中心平方距离和总距离更短。尽管 PFC 和髋关节中的 BDNF-mTOR 信号通路和突触超微结构没有改变，但在 WMT 中也观察到延长的逃逸潜伏期。总体而言，抑制 HCN1 可通过缓解抑郁和提高学习能力来缓解大鼠的 PTSD 样行为，可能与上调 BDNF-mTOR 信号通路和突触传递有关。